In an effort to investigate the contribution of nonmuscle myosin II-A (NMII-A) to early cardiac development we crossed Myh9 floxed mice and Nkx2.5 cre recombinase mice. Nkx2.5 is expressed in the early heart and later in the tongue epithelium and in a mosaic pattern in the stomach, and spleen. Mice homozygous for deletion of NM II-A (ANkx/ANkx) were born at the expected ratio but were 50% smaller than control littermates probably due to insufficient nutrition. Although the hearts developed normally, the conditionally deleted mice developed invasive squamous cell carcinoma (SCC) of the tongue as early as embryonic day 17.5. In general the mice survived for 2-3 months at which time they were sacrificed for humane reasons due to a failure to thrive. In some cases the SCC progressed slowly and the mice survived for up to 2 years of age. In order to assess the reproducibility of these results a second, independent line of Aflox mice was derived from the original, targeted embryonic stem cells. The homozygous floxed mice expressing cre in this second line were also smaller than control littermates and also developed a SCC that was indistinguishable from that of the original cell line and showed a similar timing of tumor formation and lethality. The same phenotype was observed in mice in which one allele was null for II-A and the other allele conditionally ablated by Nkx 2.5 cre expression. In an effort to rescue the phenotype by expression of a second NMHC, mice were generated in which one allele of NMHC II-A was replaced by NMHC II-B under control of the NMHC II-A promoter, but these mice also developed tumors of the tongue.